Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis

Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.

Automated summary

Although many cancers rely on autophagy for nutrient acquisition, blocking autophagy alone does not effectively inhibit tumor growth. Research has shown that blocking autophagy can lead to pancreatic ductal adenocarcinoma (PDAC) upregulating an alternative nutrient pathway, macropinocytosis (MP), allowing tumor cells to extract nutrients from outside sources. This switch from autophagy to MP, driven by the activation of transcription factor NRF2, presents a potential therapeutic strategy for inhibiting tumor growth and regression.